ABSTRACT To date, efforts to develop clinically viable in vivo chemical sensors for real-time monitoring of blood gases, electrolytes, glucose, lactate, etc. in critically ill hospital patients have been stymied by inaccurate analytical results due to sensor biocompatibility problems (cell adhesion, thrombus formation, etc.) and a high risk of infection. Our research over the past 15 years has been to explore and optimize the chemistry required to fabricate in vivo chemical sensors that slowly release low levels of nitric oxide (NO). The local release of NO mimics the chemistry that occurs at the inner walls of all healthy blood vessels (NO production by endothelium) and by immune cells (macrophages, neutrophils) and is expected to greatly enhance the biocompatibility and bactericidal properties of the intravascular sensors. This will lead to improved analytical performance of the implanted sensors and less risk of infection. Indeed, results obtained with prior NIH support have clearly demonstrated that in situ release of NO significantly reduces surface thrombus formation and improves the in vivo analytical accuracy of intravascular oxygen and glucose sensors. Very recently, a completely new type of NO releasing polymer material (S-nitrosothiol (RSNO) impregnated catheter tubing) has been developed that possesses highly desirable long-term shelf stability, long-term NO release, ease of sterilization with ETO, and low toxicity. We now wish to utilize this simple and low cost NO release chemistry to implement a new phase of research that we anticipate will lead to translation of this technology to real-time sensor technology for the intensive care units (ICU) at the end of the proposed 4-year project period. Our primary goal will be to assess whether these new materials can be readily used to fabricate catheter type electrochemical sensors (for oxygen, glucose, and lactate) that exhibit greatly enhanced in vivo analytical performance (in pigs and sheep). In addition to NO release, we will also explore the potential advantages of combining the new RSNO- impregnation chemistry with immobilized CD47 on the surface of the sensors. CD47 is a potent anti- inflammatory/anti-platelet activation agent that binds to the SIRP? receptor on surfaces of many inflammatory cells, including platelets. Optimal NO release and combined NO release/CD47 modified sensors for monitoring oxygen (PO2), glucose, and lactate will first be evaluated side-by-side (vs. corresponding non-NO release controls) in vivo within arteries and veins of anesthetized pigs (over 24 h period). The most promising approach derived from this initial screening will then be tested in fully awake sheep over 10 d periods to prove the enhanced analytical performance resulting from the antithrombotic/antimicrobial properties of this new generation of implantable electrochemical sensors. The ability to reliably measure critical care analytes in blood continuously at a patient's bedside is the ?holy grail? for biomedical sensor technology, and this goal can only be achieved when sensor performance is not compromised by biocompatibility and infection issues.